Influence of GABA on reinforcement learning in individuals with current and remitted depression

GABA 对当前和缓解抑郁症患者强化学习的影响

基本信息

批准号：
9085456
负责人：
POORNIMA KUMAR
金额：
$ 21.08万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9085456
关键词：
Abate Age Anhedonia Animal Model Animals Basal Ganglia Behavior Behavioral Brain region Characteristics Complex Computer Simulation Decision Making Depressed mood Development Disease Disease remission Dopamine Exhibits Failure Functional Magnetic Resonance Imaging Functional disorder Goals Guilt Habenula Health Human Hyperactive behavior Image Imaging Techniques Individual Intervention Lateral Learning Learning Disorders Left Link MRI Scans Magnetic Resonance Spectroscopy Major Depressive Disorder Measurement Measures Medial Mental Depression Modeling Molecular Multimodal Imaging Nature One-Step dentin bonding system Organism Participant Pattern Performance Prefrontal Cortex Prevalence Process Psychological reinforcement Punishment Recurrence Relapse Reporting Research Resolution Rewards Role Signal Transduction Social Reinforcement Symptoms System Techniques Testing Therapeutic Intervention Translating Update Ventral Tegmental Area Work animal data base burden of illness design disability dopaminergic neuron effective therapy gamma-Aminobutyric Acid heuristics innovation neural correlate neurobiological mechanism neuroimaging novel novel therapeutic intervention pre-clinical stem theories trait transmission process

项目摘要

DESCRIPTION (provided by applicant): Major Depressive Disorder (MDD) is one of the leading causes of disease burden worldwide and is characterized by a high relapse rates. In spite of decades of research, findings have not translated into a reliable model of MDD that can be used to test novel therapeutic interventions. This modest progress might partially stem from the heterogeneous nature of MDD and the fact that animal models cannot probe key symptoms of MDD, including depressed mood, guilt or rumination. Within the context of reinforcement learning (RL) theories, anhedonia, depressed mood, inability to make decisions and excessive guilt may be explained by deficits in learning about rewards and punishments and a failure to update behavior accordingly. Consistent with this theory, MDD individuals show reduced reward and increased punishment learning. Of note, reduced reward responsiveness might persist after remission, whereas punishment processing normalizes when symptoms abate, suggesting that abnormal reward, but not punishment, learning might represent a trait marker of MDD. In spite of these promising leads, the neurobiological mechanisms underlying these dysfunctions remain unknown. Critically, animal studies have shown that dopamine (DA) transmission in the ventral tegmental area (VTA) and gamma-aminobutyric acid (GABA) signals originating from the lateral habenula (LHb), as well as interactions between these systems, influences RL. These interactions modulate DA release and basal ganglia (BG) activity, which helps organisms to choose or avoid an action. Despite compelling evidence from animal studies for these interactions, these processes have not been tested in MDD. The goal of the proposed research is to fill this critical gap and take us one-step closer to developing a mechanistic model of RL dysfunction in MDD. To achieve this goal, we will integrate an innovative multi-modal molecular and functional neuroimaging approach to test RL in 60 subjects (20 HC, 20 MDD and 20 rMDD). To this end, baseline GABA levels in the BG will be measured using a novel multi-voxel MRS technique, followed by an fMRI session while participants complete a social RL task. This will allow us to investigate the neural correlates of learning deficits in MDD and the influence of GABA on RL. We hypothesize that controls will exhibit reward learning signals in the BG and punishment signals in the LHb. Consistent with our proposal that MDD is an RL disorder, we hypothesize that MDD will show blunted reward and punishment signals in the BG and LHb, respectively. This abnormal pattern in MDD will be linked to enhanced punishment and reward signals in the BG and LHb, respectively. In addition, parsing state/trait effects of MDD, we hypothesize that reward and not punishment learning deficit will be observed in rMDD. Lastly, we hypothesize that baseline GABA levels will predict RL in all groups.

描述（由申请人证明）：主要的抑郁症（MDD）是疾病繁重的主要原因，尽管有数十年的研究，但仍未转化为治疗性介入模型无法在强化学习的背景下探测MDD的关键症状，内含深度的情绪，内gui或反省。，奖励响应师缓解后，惩罚在症状减轻时进行了归一化，这表明ABAT ORMAL奖励，而不是惩罚，学习可能代表了MDD的特征标记。来自外侧Habenula（LHB）的腹侧对盖区域（VTA）ABA）信号，以及在这些系统上的相互作用，影响RL这些相互作用调节DA释放和基础神经节（BG）活动，这有助于有助于选择或避免有机体选择或避免从动物研究中，这些过程尚未在MDD中进行测试 - 在60名受试者（20 HC），20个MDD和20个RMDD中测试RL的模式和功能性神经影像学方法。 RL上的GABA。 BG和LHB，尊敬的人。